Breast cancer is the leading cause of death in women in the United States and its incidence has rapidly increased over the past decade. This Program Project focuses on the biologic mechanisms whereby hormones control cellular proliferation, modulate genotypic and phenotypic cellular changes, and influence tumor invasiveness and metastasis. Several innovative new hypotheses arising from recent results in several of our laboratories will be tested in the studies proposed. To highlight some of these, we propose that constitutive polyamine synthesis may initiate an aggressive tumor phenotype; that insulin-like growth factor binding proteins may modulate tumor cell proliferation; that variant progesterone receptors may exert negative effects on progestin action; that neutrophils may serve to create holes in basement membranes allowing tumor cells to penetrate and invade tissues; and that tumor cells may develop enhanced estradiol sensitivity upon estrogen deprivation. The overall goals of the Program Project are to examine the mechanisms which modify the mitotic, cell proliferative, and metastatic behavior of breast cancer cells growing in vitro in liquid culture, in vivo in animal systems and spontaneously in patients. Identification of these mechanisms should allow targeting of therapy to specific key processes. The strengths and expertise of the investigators participating in this Program Project facilitate focus on several key regulatory steps including polyamine metabolism (Project 1), insulin-like growth factors and their binding proteins (Project 2), progesterone receptor physiology and receptor variants (Project 3), factors controlling invasiveness and metastasis (Project 4), and regulation of responsiveness to estrogens (Project 5). Experiments address testable hypotheses by directly examining specific molecular processes, by evaluating cellular changes, and by examining biologic events such as metastases in animal models. A full understanding of the hormonal control of mitotic processes will enable identification of key steps which are bypassed in the process of evolution to aggressive tumor phenotypes. Data resulting from these studies should allow selection of several key steps for treatment intervention. While more complete blockade of aromatase is a current priority, we expect the proposed studies to identify several other steps, such as ornithine decarboxylase, as targets for therapeutic intervention.